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ABSTRACT: Prevention of left ventricular hypertrophy remains a challenge in the prevention of hypertension-induced adverse cardiac remodeling. Cardiac hypertrophy is associated with a shift in energy metabolism from predominantly fatty acid to glucose with a corresponding reduction in the expression of fatty acid oxidation enzyme genes. Although initially adaptive, the metabolic switch seems to be detrimental in the long run. This study was taken up with the objective of examining whether the stimulation of fatty acid oxidation by the activation of peroxisome proliferator-activated receptor alpha (PPARα), a key regulator of fatty acid metabolism, can prevent cardiac hypertrophy. Fenofibrate was used as the PPARα agonist. Spontaneously hypertensive rats (SHRs) in the initial stages of hypertrophy (2 months) and those with established hypertrophy (6 months) were treated with fenofibrate (100 mg·kg·d for 60 days). Cluster of differentiation 36 (CD36)-responsible for myocardial fatty acid uptake, carnitine palmitoyl transferase 1β-a mitochondrial transporter protein and medium chain acyl-Co-A dehydrogenase-a key enzyme in beta oxidation of fatty acids were selected as indicators of fatty acid metabolism. Hypertrophy was apparent at 2 months and metabolic shift at 4 months of age in SHRs. The treatment prevented cardiac remodeling in young animals but aggravated hypertrophy in older animals. Hypertrophy showed a positive association with malondialdehyde levels and cardiac NF-κB gene expression, signifying the role of oxidative stress in the mediation of hypertrophy. Expression of carnitine palmitoyl transferase 1β and medium chain acyl-Co-A dehydrogenase was upregulated on treatment. However, CD36 showed an age-dependent variation on treatment, with no change in expression in young rats and downregulation in older animals. It is inferred that the stimulation of PPARα before the initiation of metabolic remodeling may prevent cardiac hypertrophy, but reactivation after the metabolic adaptation aggravates hypertrophy. Whether the downregulation of CD36 is mediated by decreased substrate availability remains to be explored. Age-dependent paradoxical effect on the heart in response to fenofibrate, used as a lipid-lowering drug, can have therapeutic implications.
Journal of cardiovascular pharmacology 06/2011; 58(3):254-62. · 2.83 Impact Factor
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ABSTRACT: Left ventricular hypertrophy is an adaptive response to hypertension, and an independent clinical risk factor for cardiac failure, sudden death, and myocardial infarction. As regression of cardiac hypertrophy is associated with a lower likelihood of cardiovascular events, it is recognized as a target of antihypertensive therapy. This necessitates identification of factors associated with the initiation and progression of hypertrophy. Oxidative stress and metabolic shift are intimately linked with myocardial hypertrophy, but their interrelationship is not clearly understood. This study proposes to identify the temporal sequence of events so as to distinguish whether oxidative stress and metabolic shift are a cause or consequence of hypertrophy. Spontaneously hypertensive rat (SHR) was used as the experimental model. Cardiac hypertrophy was apparent at 2 months of age, as assessed by hypertrophy index and brain natriuretic peptide gene expression. Enhanced myocardial lipid peroxidation accompanied by nuclear factor-kappa B gene expression in one-month-old SHR suggests that oxidative stress precedes the development of hypertrophy. Metabolic shift identified by reduction in the expression of peroxisome proliferator-activated receptor-alpha, medium chain acyl CoA dehydrogenase, and carnitine palmitoyltransferase 1β was seen at 4 months of age, implying that reduction of fatty acid oxidation is a consequence of hypertrophy. Information on the temporal sequence of events associated with hypertrophy will help in the prevention and reversal of cardiac remodeling. Investigations aimed at prevention of hypertrophy should address reduction of oxidative stress. Both, oxidative stress and metabolic modulation have to be considered for studies that focus on the regression of hypertrophy.
Molecular and Cellular Biochemistry 01/2011; 351(1-2):59-64. · 2.06 Impact Factor
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ABSTRACT: The allelic variants of peroxisome proliferator-activated receptor alpha (PPARα) can influence the risk of coronary artery disease (CAD) by virtue of its effect on lipid metabolism. However, the role of PPARα intronic polymorphism with CAD has received little attention. The association of allelic variants G/C at intron 7 of the PPAR-alpha gene with CAD was examined in a hospital-based Indian population. PPAR genotyping was performed in 110 male patients with CAD and 120 age and ethnically matched healthy males by PCR amplification of the gene followed by restriction digestion. Presence of C allele showed a positive association with CAD (OR = 2.9; 95% CI [1.65-4.145]; P = .009) and also with dyslipidaemia (OR = 2.95, 95% CI (1.5-4.39); P < .05). Impaired lipid metabolism in carriers of the PPARα Intron 7C allele is possibly responsible for the predilection to CAD.
ISRN cardiology. 01/2011; 2011:816025.
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ABSTRACT: Cardiac hypertrophy is the first visible sign of cardiac remodeling. Oxidative stress is implicated in the etiopathogenesis of cardiac hypertrophy. In vitro studies have shown that exposure of cardiomyocytes to free radical generators induce cell hypertrophy. However, there are no studies to show that in vivo redox status can influence cardiomyocyte growth. Blood samples were collected from healthy volunteers and serum lipid peroxidation was determined as a measure of oxidative stress. Cardiac myocytes cultured from newborn rat were exposed to serum samples. A significant correlation was observed between serum lipid peroxidation and cardiomyocyte volume, indicating that in vivo oxidative stress can act as an important co-factor in mediating the hypertrophic response. This experimental system also envisages a novel approach to identify patients prone to left ventricular remodeling and identification of humoral factors mediating the changes.
International journal of cardiology 03/2007; 115(2):246-8. · 7.08 Impact Factor
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ABSTRACT: Magnesium (Mg) deficiency and oxidative stress are independently implicated in the etiopathogenesis of various cardiovascular disorders. This study was undertaken to examine the hypothesis that Mg deficiency augments the myocardial response to oxidative stress. Electrically stimulated rat papillary muscle was used for recording the contractile variation. Biochemical variables of energy metabolism (adenosine triphosphate (ATP) and creatine phosphate) and markers of tissue injury (lactate dehydrogenase (LDH) release and lipidperoxidation), which can affect myocardial contractility, were assayed in Langendorff-perfused rat hearts. Hydrogen peroxide (100 micromol/L) was used as the source of reactive oxygen species. The negative inotropic response to H2O2 was significantly higher in Mg deficiency (0.48 mmol Mg/L) than in Mg sufficiency (1.2 mmol Mg/L). Low Mg levels did not affect ATP levels or tissue lipid peroxidation. However, H2O2 induced a decrease in ATP; enhanced lipid peroxidation and the release of LDH were augmented by Mg deficiency. Increased lipid peroxidation associated with a decrease in available energy might be responsible for the augmentation of the negative inotropic response to H2O2 in Mg deficiency. The observations from this study validate the hypothesis that myocardial response to oxidative stress is augmented by Mg deficiency. This observation has significance in ischemia-reperfusion injury, where Mg deficiency can have an additive effect on the debilitating consequences.
Canadian Journal of Physiology and Pharmacology 07/2006; 84(6):617-24. · 1.95 Impact Factor
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ABSTRACT: Magnesium has a significant role in the regulation of ion transport. Marginal deficiency of Mg can therefore affect myocardial excitability and contractility. This study was taken up with the objective of examining the inotropic response of the myocardium to variation in extracellular [Mg]o and identifying the ion channels and pumps mediating the inotropic changes. Electrically stimulated rat papillary muscle was used as the experimental model and mechanical changes were recorded using a physiograph. Channel specific antagonists were used to identify the channels mediating the functional changes. Diastolic Ca2+ levels were determined in isolated myocytes by the ratiometric method using the fluorescent indicator Fura2-AM. A negative association was observed between the level of [Mg]o and force of contraction, with a peak at 0.48 mM Mg. The force of contraction in Mg deficient medium (0.48 mM) was 158% of control (1.2 mM Mg) (p < 0.001). Inotropic response to the L-type channel antagonist (verapamil-1 microm) and NaK ATPase inhibitor (Ouabain-0.3 mM) was augmented in Mg deficiency (p < 0.005), indicating activation of the channel and the pump. The response to T-type channel inhibitor (NiCl2-40 microM) was attenuated in Mg deficiency (p < 0.05). The response to the sarcoplasmic reticular Ca pump inhibitor (caffeine-10 mM) and the SR Ca2+ release channel inhibitor (ryanodine-1 microM) were not significantly affected by Mg deficiency. Diastolic level of Ca2+ increased with a decrease in Mg (p < 0.05). The observations of the study lead to the conclusion that the positive inotropic response in Mg deficiency is mediated by an increase in basal Ca2+ combined with Ca-induced-Ca release consequent to Ca2+ influx through L-type Ca channel. Variation in sensitivity to Ca channel blockers and NaK ATPase inhibitor in Mg deficiency can have pharmacological implications.
Magnesium research: official organ of the International Society for the Development of Research on Magnesium 10/2005; 18(3):163-9. · 1.52 Impact Factor
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ABSTRACT: Familial clustering is common in epilepsies, but pedigree patterns suggest a multi-factorial inheritance. Genetic liability for multi-factorial inheritance is population specific and such data are not available for the population of Kerala or other states in south India.
In this study, we have attempted to determine the genetic liability to epilepsy based on an adult population of this state.
Pedigrees were recorded for probands who reported to the Kerala Registry of Epilepsy and Pregnancy. In order to obtain a genetically matched sample for comparison and estimation of empiric risks, we have used the family history of the spouse except when the spouse was proband's relative. The ILAE criteria were followed for diagnosis and classification of epilepsy.
Data were collected on 18,419 family members of 505 probands with epilepsy (82 men and 423 women) and 10,231 family members of spouses (control). The frequency of epilepsy in first and second-degree relatives of the spouses was comparable to the population frequency (0.5%), justifying the use of this sample as control. Positive family history was observed in 22.2% of probands and 8.24% of controls (Odd's Ratio 3.2, 95% Confidence Interval 2.12-4.73). An affected first-degree relative was observed in 7.5% of probands. The corresponding figure for GE, LRE and other epileptic syndromes were 10.2%, 5.8% and 5.12%, respectively. The segregation ratio for Juvenile Myoclonic Epilepsy (JME) (1:19) was higher than that for other types of Generalized Epilepsy (GE) (1:24) and Localization Related Epilepsy (LRE) (1:52). Prevalence of epilepsy among the first-degree relatives (1.96%) was greater than the square root of the population frequency (0.51%) and was higher than that for second-degree (1.24%) and third-degree (0.64%) relatives for the probands. Probands had higher parental consanguinity (13.07%) compared to controls (6.64%). The above factors support a complex inheritance. Genetic liability to epilepsy (heritability) is greater for GE (0.6) and significantly higher for JME (0.7) compared to LRE (0.4). A limitation of this study is that the inferences are based on a predominantly adult female proband sample but no gender specific differences were identified.
The observations of this study indicate complex inheritance and the liability values are useful for genetic counseling in the local population. Further studies involving more individuals from younger age group and male gender are envisaged.
Epilepsy Research 01/2005; 62(2-3):163-70. · 2.29 Impact Factor
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ABSTRACT: This study was performed with the objective of assessing the mechanical response of the myocardium to different levels of cerium and delineation of the mechanism underlying the mediation of the functional changes. Rat ventricular papillary muscle was used as the experimental model. Isolated papillary muscles were exposed to different concentrations of CeCl3 and the force of contraction was measured using a force transducer. Experiments have revealed that the negative inotropic response to CeCl3 was proportional to its concentration. The inotropic changes were found to be completely reversible at concentrations < or =5 microM, and partially reversible at higher concentrations. Neutralization of cerium-induced inotropic changes by the superoxide anion scavenger superoxide dismutase (SOD) at concentrations < or =5 microM indicates that the mechanical changes are mediated by reactive oxygen species. At higher concentrations of Ce3+, SOD partially reversed the contractile changes. The beneficial effect of SOD was seen only if the muscles were pretreated with the scavenger prior to the addition of cerium chloride.
Biological Trace Element Research 02/2003; 96(1-3):203-8. · 1.92 Impact Factor
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ABSTRACT: Magnesium has attracted attention as an essential element with diverse roles in the regulation of cardiac contraction. Chronic suboptimal intake of the element results in hypomagnesaemia. Experimental and clinical studies indicate the possibility of a marginal decrease in myocardial magnesium compared to those with sufficient intake. Reduction in extracellular magnesium affects myocardial excitability and contractility predominantly, by modulation of the levels of other ions that have an influence on cardiac mechanics. Majority of the in vitro experiments in isolated ventricular tissue or myocytes record an inverse relation between Mg concentration and inotropic response, mediated probably by enhanced influx of Ca2+ promoting sarcoplasmic reticular Ca2+ release. Paradoxically myocardial contractility is usually compromised in animals on Mg deficient diet or on perfusion of whole heart with low Mg (< 0.5 mM) buffer. In the whole animal or organ, magnesium deficiency induced coronary vasospasm, defective energy metabolism and excessive free radical generation may be important variables acting in concert or independently to affect myocardial function. Electrical excitability is enhanced in magnesium deficiency, and arrhythmic changes are presumed to be mediated by disturbance in K+ homeostasis. Magnesium deficiency has not received the attention it deserves probably due to absence of clinical symptoms. Magnesium deficiency concomitant with stress may be of clinical significance, leading to arrhythmic, hemodynamic and ischaemic changes in the heart. Chronic magnesium deficiency is accompanied by increased free radical generation. Free radicals are known to influence myocardial excitability and contractility. Physiologic and pathologic stress also promotes free radical generation. The additive action of free radical generation in magnesium deficiency and any form of stress may be one of the reasons for enhanced sensitivity to stress in magnesium deficiency. Clinical and experimental data on the cardiac consequences of marginal magnesium deficiency being limited, a number of factors need experimental validation. For example--the extent of change in total and ionized magnesium in the serum and heart, mechanical response of the myocardium to decrease of total and ionized magnesium in the intra- and extracellular milieu; the extent of free radical generation in magnesium deficiency and the cardiac consequence; and also the additive effect of magnesium deficiency and different forms of stress.
Magnesium research: official organ of the International Society for the Development of Research on Magnesium 12/2002; 15(3-4):287-306. · 1.52 Impact Factor
